Within-Trial Decisions

Site: EUPATI Open Classroom
Course: Clinical Trials and Trial Management
Book: Within-Trial Decisions
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Date: Friday, 2 June 2023, 5:02 AM

1. Introduction

(This section is organised in the form of a book, please follow the blue arrows to navigate through the book or by following the navigation panel on the right side of the page.)

There are many different types of decision that may need to be made once a clinical trial has begun. Some are routine decisions in managing a trial, but especially in case of safety issues, some decisions may have a major impact on the conduct of the trial, and could even result in the termination of the trial.

These decisions can also result in the modification of the study protocol, e.g. the trial rationale, procedural aspects, inclusion and exclusion criteria, medication and dose to be used, as well as many other details.

There are many different issues that may arise during the conduct of the trial that may necessitate immediate decision-making, such as premature trial termination. Such issues may be related to the emergence of new scientific evidence, as the trial progresses, e.g. interim trial results may give an indication on whether an intervention is beneficial or not. Trial data, and their interim analysis, often necessitate a reassessment of the scientific validity of the trial, along with an examination of what is clinically meaningful and ethically sound. This reassessment may result in the modification or termination of the trial, when evidence arises that the original assessment of benefit-risk to the patient is no longer favourable, or when the beneficial effect is so evident that it is ethically unsound not to give the treatment to all the patients.

This requires continuous observation of the clinical trial participants and a general oversight of the study conduct, which is ensured by trial monitoring, implemented and maintained by the sponsor. Monitoring ensures that the rights and overall wellbeing of the patients are safeguarded, including the setup of reporting processes that indicate if there is a serious safety matter requiring immediate attention, for example, an unexpected serious safety signal.

A safety signal, according to the Council for International Organizations of Medical Sciences (CIOMS), is information that arises during the trial suggestive of a causal association between the intervention (e.g. the medicinal product being tested) and an event or set of related events, either adverse or beneficial, which is judged to be sufficient to justify further action.

2. Code-breaking (unblinding)

In most pharmaceutical companies and contract research organisations (CRO) there is a procedure for unblinding an individual participant’s treatment allocation while the trial is still ongoing. This happens if there is a medical emergency or serious medical condition during a clinical study when clinicians (investigators) cannot manage treatment without knowledge of the participant’s study treatment.

To provide the documentation of the unblinding process is a regulatory requirement for study sponsors. This is usually done in a standard operating procedure (SOP) and there may be a guidance document or process flow to support the SOP.

In some organisations there is a call-centre or automated system to manage the process on behalf of the study sponsor. In many organisations the study staff who may receive a call from a healthcare provider, particularly out-of-hours, will be trained to access the system, identify the treatment allocation and complete the required documentation of the case.

There may be situations where special product-specific circumstances exist, such as a known risk for overdose or a potentially harmful interaction with other medicines. These cases require the availability of an on-call doctor. The process would then be modified to ensure that a procedure is in place to ensure that an on-call doctor discusses the request for unblinding, prior to its execution. This is to protect the patient from any serious impact of removing a treatment that requires dose titration, or from a potential treatment that may react badly with the study medicine that has been taken.

Trial sites are provided with specific training on the unblinding procedure and ‘patient cards’ (or equivalent) are provided to the patient to enable emergency unblinding by anyone who may happen to see the patient such as clinicians not involved with the trial in emergency rooms. The patient cards carry information about the clinical trial in which the patient is taking part, including clinical trial name and number, the principal investigator’s and institutions contact details, and the number to call for emergency unblinding. The patient is instructed to offer the card to any health worker other than those related to the trial in which they are participating.

Once the patient blind is broken, many patients will be required to discontinue the trial because of the possible bias. If there are too many cases where the treatment allocation has been disclosed during the study, the statistical integrity of the trial may be jeopardised. As additional safeguard, the trial-related clinical staff are often requested to discuss the need for knowing the patient’s treatment in case they have to treat an emergency with the medical monitor/on-call doctor, prior to making the call to the automated system or helpdesk to break the blind.

3. Premature Termination

There are many reasons why a study may be terminated early, but in most cases these are pre-determined scientific or medical reasons. For example:
  • Emergence of a serious adverse reaction (ADR) where the risk to the patient is considered to be too great to continue, or
  • A pre-planned interim analysis that clearly identifies superiority of one treatment or lack of effect of a treatment.
In most cases stopping a clinical trial requires the approval of senior medical management (in most pharmaceutical companies this is the chief medical officer). There may be cases where recruitment is proving so challenging that it is considered unethical to continue the trial. In these situations, it is unlikely that the scientific question will ever be answered. The regulatory authorities that approved the study need to agree to the termination.

In most organisations conducting clinical trials there are detailed instructions within the protocol on how interim analyses should be approached and what the statistical and decision-making processes will be to evaluate the data. Under no circumstances can an interim analysis be planned to have a quick check of the data during a trial. All interim analyses have to be clearly defined; including the time point when the data will be analysed and why.

In the majority of cases an interim analysis is usually conducted to:
  • Identify whether there is an imbalance between the safety profile of the groups and therefore potentially placing some patients at risk, or
  • To assess whether there is an imbalance in efficacy against a comparator treatment.
In all cases where the possibility exists to terminate a trial following an interim analysis, there has to be clearly defined stopping rules detailed in the protocol. Stopping rules need to be described in the informed consent documentation as well. To decrease any bias, the decision on whether the data produced from an interim analysis meets the stopping criteria should be made by an independent committee.

4. Data Safety Monitoring Boards (DSMB)

Data safety monitoring boards (DSMB) also go under different names like Data Monitoring Committee (DMC), Data Monitoring Board or Data Safety Monitoring Committee. EU legislation uses the term DMC, but EUPATI will use the term DSMB based on the frequency of use seen, even if the original document used a different term.

A DSMB is a group of independent experts external to a study assessing the progress, safety data and, if needed critical efficacy endpoints of a clinical study. In order to do so a DSMB may review unblinded study information (on a patient level or treatment group level) during the conduct of the study. Based on its review the DSMB provides the sponsor with recommendations regarding study modification, continuation or termination. (1)

A DSMB may be set up for different reasons, here are some:
  • In case of life-threatening diseases from an ethical point of view.
  • In case of long-term trials even in non-life-threatening diseases for monitoring safety.
  • In case of prior knowledge or strong suspicion that a treatment under consideration has the potential to harm patients.
In case of a specific study design, e.g. in the context of pre-planned interim analyses for early stopping (either for futility or for positive efficacy) or in case of complex study designs where a possible modification of the study design based on unblinded interim data is intended.

4.1. Function of Data Safety Monitoring Boards (DSMB)

Although DSMB members are selected and appointed by the sponsor, all members should be completely independent of any ties to the trial that may affect their objectivity. Possible conflicts of interest (e.g. political, market, financial influences) should be taken into account. Any compensation paid to DSMB members should be reasonable to ensure there is no conflict of interest for members. Thus, any recommendation made by the DSMB should be free from bias.

DSMB operating procedures (how it works and communicates with other study participants – data centres, sponsor, etc.) must be established and described before the start of the trial. Operating procedures should also describe how the integrity of the study with respect to preventing dissemination of unblinded study information is ensured. The size and composition of the DSMB depends on the type of trial to be executed. Members with clinical and statistical experience must alwaysbe included, and additional expertise in ethics and the specific disease area is often required. This is where community or patient representatives might be invited. Terms and conditions of appointment should be transparent and procedures should be clearly defined and well documented.

Although it seems a very logical step in protecting the participants’ or patients’ best interest, the inclusion of expert patients or other representatives of patient organisations in DSMB’s is a relatively recent development. E.g. the European Community Advisory Board (on HIV/AIDS) has been dispatching members into DSMBs regularly since 2010. Patient representatives are equal participants of DSMBs, their work is also bound by strict confidentiality, however, they will import their experience of living with the given disease from a very special aspect – that of the patient themselves.

While in general, safety monitoring is the major task for a DSMB, other aspects of a clinical trial (e.g. trial integrity, design aspects) might also be assessed.

The DSMB will convene both open and closed meetings on a frequency laid out in the operating procedures at the start of the trial; this can be time based or when the pre-determined analysis points have been met, e.g. 50% patients reaching six months treatment. Usually only a sub-set of data that is most pertinent to the question being asked of the DSMB is analysed and often still in blinded fashion, if the study is blinded. The operating procedures will contain rules that detail when the DSMB may request further data to be analysed or the blind to be broken.

A report by the sponsor to the DSMB, (along with the full safety and efficacy data) may contain an open and a closed section, containing blinded and non-confidential data, and unblinded confidential data, respectively. The operating procedures should also clearly state the parties allowed to have access to any unblinded data.

Finally, the process of how the DSMB will arrive at a recommendation, must be documented. Ideally, recommendations should be made after reaching consensus, wherever possible, otherwise by vote. A recommendation that will result in modification, suspension or termination of a trial must be clearly supported by the reasons why the DSMB reached such a decision.

The proper communication of its recommendations is a major responsibility for a DSMB. If changes in the study conduct are recommended by a DSMB, sufficient information should be provided to allow the sponsor to decide whether and how to implement these recommendations. The implementation of any DSMB recommendation is solely the responsibility of the sponsor who has no obligation to follow them (in whole or in part).

Safety monitoring is an essential and integral part of any trial; nevertheless, not all clinical studies require a DSMB. DSMBs may be critical for studies intended to save lives, prevent serious disease progression or reduce the risk of a major adverse health outcome.

EMA Guideline on data monitoring committees Doc. Ref. EMEA/CHMP/EWP/5872/03 (1) describes the process for assessing the need for a DSMB. DSMBs are particularly important in studies where interim data analysis is required to ensure the safety of research participants.

As there are currently no accepted standards on what constitutes conclusive evidence, transparency in the decision-making process is paramount. A way to achieve this would be for the DSMB, after the trial has been completed, to publicly disclose the full rationale for their recommendations (2).

5. References & Further Reading


  1. EMA guideline on data monitoring committees Doc. Ref. EMEA/CHMP/EWP/5872/03: Available at: Guideline on Data Monitoring Committee (europa.eu)

  2. US Food and Drug Administration. Guidance for Clinical Trial Sponsors - Establishment and Operation of Clinical Trial Data Monitoring Committees. Last accessed June 15, 2014: Available at: Establishment and Operation of Clinical Trial Data Monitoring Committees | FDA
Further Reading

  • Fleming TR, Hennekens CH, Pfeffer MA, DeMets DL. Enhancing Trial Integrity by Protecting the Independence of Data Monitoring Committees in Clinical Trials. J Biopharm Stat. 2014 Jun 13.

  • Katz ML, Archer LE, Peppercorn JM, Kereakoglow S, Collyar DE, Burstein HJ, Schilsky RL, Partridge AH. Patient advocates' role in clinical trials: perspectives from Cancer and Leukemia Group B investigators and advocates. Cancer. 2012 Oct 1;118(19):4801-5. Available at: Patient advocates' role in clinical trials (wiley.com)

  • Institute of Medicine. A National Cancer Clinical Trials System For The 21st Century. Reinvigorating the NCI Cooperative Group Program. Washington, DC: National Academies Press; 2010.

  • http://ec.europa.eu/research/health/pdf/event05/sue-pavitt_en.pdfs